Since a polysaccharide is a safe polymer derived from the living body, application of modified substances of the polysaccharide to various medical materials has been attempted.
An example of such a medical products disclosed in Eur. J. Pharm. Sci., 2002 March; 15(2): 139-48, where a polysaccharide gel is made by crosslinking chondroitin sulfate using a diglycidyl ether as a crosslinking agent. In this type of process, the crosslinking reaction takes place together with the reaction of chondroitin sulfate with the crosslinking agent. It has been found that it is difficult to remove the unreacted crosslinking agent from the crosslinked-gel after completion of the reactions. This deficiency may cause problems as it has been confirmed by experiments that disorder happens in the liver when a sponge-formed or gel-formed crosslinked-polysaccharide in which the crosslinking agent is insufficiently removed is applied, for example, into the abdominal cavity as an antiadhesive agent. Accordingly, removal of a crosslinking agent is important. When a crosslinked-polysaccharide is spongy, removal by washing is relatively easy but, when it is in the form of gel or film, the crosslinking agent is incorporated into the inner area whereby its removal is very difficult.
In view of the above, it has been proposed to synthesize a polysaccharide which is photoreactive. In particular, it has been proposed as a preliminary step, to bind a polysaccharide to a compound which already has a photoreactive crosslinking group (agent) chemically bonded thereto. Thus, upon irradiation, the photoreactive crosslinking group will facilitate crosslinking of the polysaccharide. However, prior to irradiation, such a “photoreactive polysaccharide” is capable of forming a solution so as to easily remove the unreacted crosslinking group or agent. Use of such photocrosslinked-polysaccharides as various medical products has been attempted.
For example, U.S. Pat. Nos. 5,462,976, and 5,763,504, disclose that a photoreactive glycosaminoglycan derivative is produced by first bonding to a crosslinking agent such as cinnamic acid, thymine or coumarin into glycosaminoglycan which is a natural polymer. The resulting compound can then be purified to remove the unreacted crosslinking agent. After purification, the photoreactive polysaccharide can then be subjected to photocrosslinking using ultraviolet light to produce a photocrosslinked-glycosaminoglycan, to be used as an antiadhesive agent and a carrier for sustained-release of a drug.
Also, U.S. Pat. Nos. 6,025,444 and 6,107,410, disclose photocrosslinked products derived from photoreactive-hyaluronic acid derivatives in which, before photocrosslinking, cinnamic acid is first bound to hyaluronic acid via a spacer compound selected from: an amino acid or derivatives thereof; a peptide; amino alcohol; and, diamine.
U.S. Pat. No. 6,031,017, discloses a crosslinked hydrogel having the specific physical property which causes a preventive action for tissue adhesion. The hydrogel is produced by ultraviolet radiation of a photoreactive hyaluronic acid derivative. In the derivative, a photoreactive crosslinking group is chemically bound to a functional group of hyaluronic acid.
Other examples of photocrosslinked polysaccharides proposed for use as a medical material are: (WO02/060971 which discloses a photocrosslinked-polysaccharide sponge which can be utilized for a medical material); (U.S. Pat. No. 6,602,859, discloses a photocrosslinked hyaluronic acid proposed for use as a medical material or product). The photocrosslinked hyaluronic acid is made from a photoreactive hyaluronic acid which is proposed to have enhanced hydrophilic and filtering properties as an aqueous solution.); (JP-A-56-147802 which discloses a heparin derivative which is highly useful as an intermediate of a polymer for medical applications. The derivative is produced by reacting heparin with glycidyl acrylate or glycidyl methacrylate.); and, (U.S. Pat. No. 6,586,493 which discloses a crosslinked-product of a mixture hyaluronic acid and either glycidyl acrylate or glycidyl methacrylate bound to a non hyaluronic acid polysaccharide).
In addition to the above considerations for medical products based upon crosslinked polysaccharides, especially medical products for use as an antiadhesive agent, are the consideration that the products have a sufficient barrier effect and an appropriate degrading property. There have been repeated dilemmas caused by conventional photocrosslinked-polysaccharides used as an antiadhesive agent. In particular the product's residence in vivo becomes undesirably long if a barrier property is made high, while, if an appropriate degrading property is given, a sufficient barrier effect is not achieved. For example, when a sponge or a sheet made with a conventional photocrosslinked-polysaccharide gel having a high barrier effect is used as an antiadhesive agent, undesirable side effects can occur because the gel remains in the living body too long because of late to metabolization. Accordingly, there has been a demand for the development of medical products, particularly an antiadhesive agent, having sufficient strength and barrier effect in spite of desirable or controllable degradability in vivo.
In order to find a photocrosslinked-polysaccharide having a high barrier effect and an appropriate degrading property, the present inventor has carried out intensive studies and, as a result, has developed a photocrosslinked polysaccharide which when used as a medical product has sufficient barrier effect and an excellent early-stage degrading property. It was found that these desirable properties are provided by photocrosslinking a polysaccharide to which a specific crosslinking agent is bound.